Pharmaceutical composition intended in particular for the prevention and the treatment of radiomucositis and chemomucositis

ABSTRACT

The invention concerns a pharmaceutical composition designed to adhere to a mucous membrane for preventing or treating radiotherapy-related and chemotherapy-related mucositis, induced by radiotherapy or combined radiochemotherapy, comprising an effective amount of an antiradical compound mixed with a vehicle, which is liquid at room temperature and gels at the mucous membrane temperature and capable of adhering to the mucous membrane by its gelled status.

CROSS REFERENCE TO RELATED APPLICATIONS

This application represents entry into the United States under 35 U.S.C. § 371 of International Application PCT/FR99/01760, filed Jul. 19, 1999, which in turn claims priority of the French national application serial no. France 98 09 230, filed Jul. 20, 1998.

The present invention relates to a pharmaceutical composition intended in particular for the prevention and the treatment of radiomucositis and of mucositis induced by anticancer polychemotherapies.

From the data collected during the period 1987–1992 among its member countries, the World Health Organization (WHO) calculated (for the year 1994) an estimation of the incidence of cancers, according to gender, on a global scale (World Health Organization: World Health Statistics Annuals, 1987–1992—Geneva, Switzerland, WHO): in men, the location characterized by the highest incidence is the prostate (32%); in women, the highest incidence is breast cancer (32%). In men, cancers of the head and neck as well as of the oropharyngeal cavity have an incidence of close to 6% and the incidence of colorectal cancers is 12%. In women, the incidence of cancers of the “head and neck, and the oropharyngeal cavity” is 5% and that of colorectal cancer 13% while the incidence of uterine cancers is 8%. These figures speak for themselves and show immediately the extent of the problem posed by the taking into account of the side effects of antimitotic treatments used, in particular antiproliferative polychemotherapies and radiotherapy.

Depending on their location, cancer therapy frequently involves medium- or high-energy radiotherapy either as a first line treatment, or as an adjuvant therapy to surgery and chemotherapy. Radiotherapy is in particular widely used for the treatment of certain locations: head and neck; brain; oropharyngeal cavity; oesophagus and stomach; large intestine and rectum; uterus. In 1994, the incidence of new cases of cancer in these locations was estimated by the National Cancer Institute (NCI), for the population of the United States:

head and neck, brain: 17,500 new cases oropharyngeal cavity: 29,600 new cases larynx: 12,500 new cases oesophagus and stomach: 35,000 new cases colon and rectum: 150,000 new cases uterus: 46,000 new cases.

By virtue of the advances in computerized axial tomography, the determination of irradiation fields, the kinetics of irradiation as well as the rates of radiation doses have been improved regularly. Accordingly, for “head and neck” cancers, it is now known that the period between surgical exeresis and radiotherapy should not exceed 6 weeks and that any interruption in the radiotherapy—even in the event of severe adverse effects—is prejudicial to its efficacy. Even more, it is known that certain tumours require an acceleration of the radiotherapy (dose intensification) in order to reach more effectively a larger number of tumour cells when these are in the dividing phase: this is hyperfractionated radiotherapy. In the same spirit, the constant search for potentiation of the therapeutic effect has led to the evaluation of alternate radiochemotherapy and to protontherapy which allows the irradiation to be very finely focused.

Radiotherapy-based irradiation of a cancer of the oesophagus or of the larynx leads to the appearance of a painful dysphagia, a source of an intense functional discomfort (which can cause substantial loss of weight), by attack on the mucous membrane by the ionizing radiation. Likewise, the irradiation of abdominal adenopathies or tumours induces complications at the gastric level. Nausea and vomiting are the most frequent manifestations. However, early epithelial impairments and in particular painful ulcerations, which are often very severe and which may persist after the end of the radiotherapy cycle, may appear.

However, it is the buccal complications of cervicofacial radiotherapy which are the most typical. The initiation of this treatment is marked by a more or less intense mucosal reaction—oropharyngeal mucositis—which is similar to a very severe skin erythema, following a serious burn induced by prolonged exposure to intense ultraviolet radiation of solar origin (very hot summer season or tropical countries). The specificity of the radiomucositis, in particular oropharyngeal radiomucositis, is linked to the specificity of the mucous membrane and to its fragile nature. Unlike the skin integuments which are thick covering tissues, the mucous membranes (buccal, gingival, gastric, intestinal, uterine, vaginal and anorectal) are very fragile because they consist of cellular structures lacking keratin, which are very rich in water and in blood vessels. In such tissues, the molecular agitation induced by high-energy radiation causes an extremely rapid disorganization of the cellular organization which is at the origin of the destruction of the mucous membrane. Unlike the skin tissue, these mucous membranes are not resistant to attacks of this type and do not have any physiological system of protection (e.g.: lipohydrophilic character; rate of renewal, and the like) which is effective against the damage caused by the energy received during each irradiation cycle.

The most deleterious consequences of the oropharyngeal mucositis are the functional discomfort the perception of which can be extremely variable from one patient to another, this discomfort not being linked to the intensity of the clinical symptom. The radiomucositis may therefore be highly crippling, in particular when the erythema is followed by an oedema and then by erosions of the mucous membrane which can, in addition to intense pain, seriously hamper food intake.

In addition, irradiation of the salivary glands, taken in the target volume, causes drying of the mouth, which is often intense and long lasting, or even permanent. In addition to the discomfort of hypoptyalism or of xerostomia (deprivation of saliva), which can also be extremely badly felt, multiple caries may also develop rapidly. At this stage, the major risk of dental lesions, apart from loss of teeth, is requiring the extraction of the tooth on an irradiated bone with the constitution of an osteoradionecrosis, which is essentially mandibular. Thus, the complications of post-irradiation xerostomia are mycoses, repeated bacteria infections, multiple caries and osteoradionecroses and these are frequent, in particular, during radiotherapies of the upper aerodigestive tracts.

Because the mucositis can be aggravated by several cofactors (e.g.: associated chemotherapy [5-FU, cisplatin], nicotine addiction, alcoholism, poor dentibuccal hygiene, and the like) the risks induced by the appearance of radiomucositis may be extremely serious. They therefore justify the search for means for the effective prevention of the erythematous mucosal reaction caused by ionizing radiation.

The authors of the present invention were interested in this question because the current therapeutic means for the prevention or treatment of radiomucositis are not optimized. Indeed, they involve essentially the simultaneous administration of analgesics (e.g.: aspirin), of antifungals (e.g.: amphotericin B, miconazole), of a contact anaesthetic (e.g.: xylocalne) and of mouthwash (based on chlorhexidine and hexamidine) which are systematically repeated.

This is how the idea emerged to develop a composition which is liquid at room temperature, but which is capable of adhering to a mucous membrane because of its passage to the gelled state when the temperatures reaches the temperature of the mucous membrane and which contains substances with anti-free radical activity, while not interfering with the energy emitted by each dose of radiotherapy. Developed to prevent the appearance of buccopharyngeal mucositis following radiotherapy for “head and neck” cancers, this concept of a specifically adapted pharmaceutical preparation can also be applied to other forms of mucositis which are induced by radiotherapy and/or chemotherapy or alternatively combined radiochemo-therapy in the treatment of cancers such as those of the colon, the rectum and the anus or when these therapies incidentally reach the vaginal mucous membrane.

The subject of the present invention is thus a pharmaceutical composition intended in particular for the prevention and the treatment of radiomucositis and of chemomucositis, comprising an effective quantity of a compound having anti-free radical activity in the form of a mixture with a vehicle which is liquid at room temperature and which gels at the temperature of the mucous membrane and which is capable of adhering to the mucous membrane because of its gelled state.

The compound having anti-free radical activity may be in particular chosen from:

-   -   1—flavonoids of natural origin, for example:         -   i) flavonols or flavonolols, among which:             -   a rutoside: rutin (quercitin 3-O-rutino-side),                 quercitrin (quercetin 3-O-rhamno-side), isoquercitrin                 (quercetin 3-O-glucoside),             -   diosmin (diosmetin 7β-rutinoside), astragalin                 (kaempferol 3-O-glucoside), kaempferol 3-O-rutinoside,                 myricitrin (or myricetin 3-O-rhamnoside),             -   robinin (or kaempferol 3-O-robinoside 7-rhamnoside),             -   kaempferitrin (or kaempferol 3,7-O-dirhamnoside),             -   nobiletin,             -   tangeretin.         -   ii) flavones, among which:             -   rhoifolin (or apigenin 7-O-neohesperido-side), luteolin                 7-O-glucoside,             -   scutellarin (or scutellarein 5-O-glucoside),             -   pectolinarin (or pectolinarigenin 7-O-rutoside),             -   galuteolin (or luteolin 5-O-glucoside),             -   acaciin (or acacetin 7-O-rhamnoglucoside),         -   iii) flavanones, among which:             -   liquiritin (or liquiritin 4′-O-glucoside), naringin (or                 naringenin 7-O-neohesperido-side), hesperidin (or                 hesperetin 7-O-rut-inoside),             -   eriodictin (or eridictiol 7-O-rhamnoside)     -   2—isoflavonoids of natural origin, for example:         -   formononetin 7-O-glucoside (or ononin), afromosin             7-O-glucoside (or wistin),         -   genistein (or genistein 7-O-glucoside), daidzin, glycitin,         -   genistein 6-O-malonylglucoside, daidzein             6-O-malonylglucoside, genistein 6-O-acetyl-glucoside,         -   iridin (or irigenin 7-O-glucoside),         -   irisolone,         -   tectoridin (or tectorigenin 7-O-glucoside) or shekanin.     -   3—tocopherols;     -   4—polyphenols and plant extracts containing polyphenols such as         procyanidolic oligomers, extracts of St. John's wort, of         Kallanchoe pinnata, of camomile, of pine bark, of tea, of         Centella asiatica, extracts of larch, of edelweiss,     -   5—vitamins: for example, vitamin A, a carotenoid, alpha-lipoic         acid,     -   6—the active fractions of vegetable oils such as alpha-lupaline,         hierogaline,     -   7—butylated hydroxyanisole, butylated hydroxytoluene.

The vehicle which is liquid at room temperature and which gels at the temperature of the mucous membrane may consist in particular of an aqueous dispersion or solution of a mixture of:

-   -   a—0.05 to 5% by weight (preferably from 0.1 to 3% by weight) of         an agent conferring viscosity;     -   b—1 to 20% by weight (preferably from 5 to 20% by weight) of an         agent modifying the viscosity according to the temperature.

i) The agents conferring viscosity may be chosen in particular from the following compounds:

-   -   colloids or hydrocolloids (polysaccharide substances and related         substances):         -   galactomannans and derivatives: guar gum, carob gum, tara             gum, and the like         -   starch and derivatives         -   gum arabic, tragacanth gum, karaya gum, and the like         -   pectins and derivatives of pectin, and the like         -   alginates: alginic acid, sodium alginate, sodium/calcium             alginate, and the like         -   carrageenans and derivatives, and the like         -   cellulose and derivatives: carboxymethyl-cellulose (CMC),             sodium carboxymethylcellulose, calcium CMC, methylcellulose,             hydroxy-propylcellulose, hydroxypropylmethylcellulose,             hydroxyethylcellulose, and the like         -   high-molecular weight dextrans         -   xanthans and derivatives, and the like         -   hyaluronic acid and derivatives, chitin and chitosan and             their derivatives, and the like     -   polymers of acrylic and methacrylic acids and derivatives:         polymethacrylate, carbophilic carboxyvinyl polymer (carbopol,         carbomer), polyhydroxyethyl methacrylate,     -   polyvinyl derivatives, polyvinylpyrrolidone,         poly(vinylpyrrolidone and vinyl acetate), polyvinyl         acetatephthalate, polyvinyl alcohol,     -   high-molecular weight polyethylene glycols,     -   polyacrylamide and derivatives,     -   polymers of maleic acid, such as for example: copolymer of         polyvinyl ether/maleic acid, sodium/calcium salts of the         polyvinyl ether/maleic acid copolymer complex,     -   sodium polystyrenesulphonate,     -   inorganic derivatives: silica and silicate and silicone         derivatives and the like

ii) As examples of agents modifying the viscosity according to the temperature, there may be mentioned:

-   -   poloxamers (e.g.: poloxamer 188, poloxamer 407 and the like) and         poloxamines     -   compounds of the divinylbenzenesorbitol type (disorbene), which         are soluble in lipophilic medium.

Compositions which have a viscosity of less than 200×10⁻³ Pa·s at room temperature (20° C.) and a viscosity greater than 2000×10⁻³ Pa·s at 35–37° C. are preferred, the viscosity being determined with an LV type Brookfield viscometer/LV4 rotor/speed of rotation 0.5 rpm/reading after 15 seconds.

By way of example, a solution according to the invention which contains a concentration of agent conferring viscosity—c=1.7% of hydroxymethylpropyl-methylcellulose (HPMC),—with 5% of rutin and 14% of poloxamer 407, exhibits the following behaviour on raising the temperature:

Temperature (t ° C.) Viscosity (10⁻³ Pa · s) 25 314 30 1433 35 3027

Thus, at 25° C. the solution is fluid (viscosity of the order of 300×10⁻³ Pa·s) and the gelling is obtained by passage to a temperature of 30° C., then 35° C. (the viscosity is multiplied by 10 between 25 and 35° C.)

The aqueous compositions preferably have pH values which are compatible with the mucous membranes (in general between pH 7 and 8).

The subject of the present invention is also compositions in solid form intended to be mixed with water to form a solution which is liquid at room temperature and which is capable of forming a gel on contact with the mucous membrane to be protected. For the gastric mucous membrane and/or the intestinal mucous membrane, it is thus possible to have solid forms such as a powder or a granule, or alternatively granules which give, upon addition to a liquid vehicle, a liquid composition (example: powder for syrup, for suspension or solution for oral administration to be prepared immediately before use). The compositions may also be provided in the form of bare tablets or granules to be dissolved in water just before use.

The compositions according to the invention may contain other active ingredients combined with the compounds having anti-free radical activity and in particular those belonging to the following pharmacotherapeutic families:

-   -   analgesics and antispasmodics (paracetamol, aspirin, codeine,         morphine, atropine, loperamide, phloroglucinol, and the like),         anaesthetics (xylocalne, lidocaine) and antiseptics         (chlorhexidine, hexamidine),     -   anti-inflammatory agents belonging to the corticoid family         (prednisolone, triamcinolone, and the like) or oxicams (e.g.:         piroxicam, and the like),     -   anti-ulcer agents (antihistamines H₂, prostaglandins and         derivatives, proton pump inhibitors such as omeprazole,         pantoprazole, lanzoprazole),     -   antacids and gastrointestinal dressings (aluminium phosphate,         aluminium and magnesium hydroxide, clays (diosmectites,         actapulgites, and the like),     -   medicaments for gastrooesophageal reflux and for digestive         motivity (sodium alginate, sodium bicarbonate, metoclopramide,         and the like),     -   antiemetics (benzamides, antihistamines H₁, setrons, and the         like),     -   antidiarrhoeals (loperamide, and the like),     -   antifungal with digestive targets (amphotericin B, nystatin,         tioconazole, itraconazole, econazole, butoconazole, and the         like),     -   medicaments for digestive functional disorders (e.g.: cisapride)         and for intestinal transit,     -   intestinal antibacterials (aminoglycosides, nitroimidazoles,         polymyxines, and the like) and antivirals (e.g.: acyclovir),     -   products recognized for their soothing and/or cicatrising         properties such as: biotin, polyphenols, glycyrrhizinic acid,         thymol, eucalpytol, and the like, and extracts of plants rich in         glycyrrhetinic acid, pantothenol, allantoin and derivatives,     -   vitamins: of group B (B1, B6, B12), nicotinamide, biotin,         pantothenic acid,     -   products correcting hypoptyalism and regulating saliva         secretion: pilocarpine, anetholtrithione,     -   peptides and enzymes: elastin, collagen, glutathione, catalase,         endonuclease, which can contribute to the repair of tissues         lesioned by irradiation.

The following examples illustrate the present invention.

I—Compositions for the Buccal Mucous Membrane

Without being limiting, and to illustrate the invention, the following preparations may be presented as examples:

Percentages Examples 1 2 3 4 Water-soluble 2 to 10 2 to 10 2 to 10 2 to 10 rutoside Pilocarpine — 1 to 5  — 1 to 5  hydrochloride Poloxamer 407 14.0 5 to 20 5 to 20 5 to 20 HPMC 1 to 3  1 to 3  1 to 3  1 to 3  Flavouring 0.1–0.5 0.1 to 0.5 0.1–0.5 0.1 to 0.5 Alpha- — — 0.01 to 0.05 0.01 to 0.05 tocopherol Buffer pH 7.8 qs 100 100 100 100

These compositions constitute solutions of thermoreversible consistency: fluid at room temperature (20° –25° C.), viscous at the temperature (35–37° C.) of the physiological cavities. Thus, the viscosity at room temperature (25° C.) of a composition combining 5 to 20% of poloxamer 407 and 1 to 3% of HPMC polymer (that is 6 to 23% of gelling agents) may be sufficiently low (150 to 300×10⁻³ Pa·s) to allow easy propulsion (by the delivery system) and then an effective gelling on the mucous membrane to be protected (by passage of the viscosity to 2000–21,000×10⁻³ Pa·s when the temperature increases between 30 and 35° C., for example).

II—Composition for the Digestive Mucous Membrane

1—Gellable Liquid Composition

As nonlimiting examples, there may be mentioned:

Percentages Examples 5 6 7 8 Rutoside  2 to 10 1 to 5 0 to 5 0 to 5 Amphoter- —   1 to 2.5 — — icine B Miconazole — — 1 to 5 — Allantoin 0 to 1 0 to 1 0 to 1 — Biotin    0 to 0.050 0 to    0 to 0.050 0 to 0.050 0.050 Dexpanthenol 0 to 1 0 to 1 0 to 1 0 to 1 St John's — — — 0 to 5 wort (aqueous extract) Kallanchoe — — — 0 to 5 (aqueous extract) HPMC 1 to 3 1 to 3 1 to 3 1 to 3 (Methocel E4M) Poloxamer  6 to 20  6 to 20  6 to 20  6 to 20 407 (Lutrol F127) Sweetener/ qs qs qs qs flavouring Preservatives qs qs qs qs Water qs 100 100 100 100

2 Granules to be Dispersed in Water

At the temperature of the gastrointestinal tract, this composition forms a gel adhering to the villosities of the mucous membrane.

(mg) Examples 9 10 11 12 Diosmin 500 500 500 500 Extract of Centella 20 to 50 — — asiatica Hydroxypropyl- 150 150 150 150 methylcellulose (HPMC) Xanthan gum 250 250 250 250 Calcium carbonate 1000  1000  500 — Aldioxa* — — 900 — Alcloxa** — — 100 — Poloxamer 407 1500  1500  1500  1500  Aluminium hydroxide — — — 400 Magnesium hydroxide — — — 400 Flavouring qs qs qs qs Xylitol 1000  1000  1000  1000  *dihydroxyaluminium allantoinate **chlorhydroxyaluminium allantoinate (for one sachet to be dispersed in a volume of 100 to 200 ml of water)

EXAMPLE 13 Granule to be Dispersed in Water (Preparation for Immediate Use)

At the temperature of the gastrointestinal tract, this composition, in mg for one sachet to be dispersed in 100 ml of water at the time of use, also forms a gel adhering to the villosities of the mucous membrane:

OPC* 200–500 Alpha-lipoic acid  0–20 Polyvidone 200 β-cyclodextrin 1000–3000 Hydroxypropylmethylcellulose 100 Poloxamer 407 1000  Flavouring/sweetener qs *procyanidolic oligomers (extract of grape seed and of pine bark)

III—Composition for the Rectal Mucous Membrane

Two examples of ready-to-use thermogellable viscous solutions are given below:

Examples 18 (in %) 19 (in %) Rutosides  2 to 10 1 to 5 Dexpanthenol — 1 to 5 Butylated hydroxytoluene —  1 to 10 Alpha-tocopherol — 0.01 to 0.05 (HPMC) Methocel E 4M 1 to 3 1 to 3 Poloxamer 407  5 to 20  5 to 20 Purified water qs 100 100

IV—Compositions for the Vaginal Mucous Membrane

Three nonlimiting examples of solutions which gel at the temperature of the mucous membrane are given below:

Examples 20 (in %) 21 (in %) 22 (in %) Rutosides 0.5 to 10  0.5 to 10  0.5 to 10  Butoconazole 1 to 5 — — nitrate Econazole nitrate — 1 to 3 — Thioconazole — — 2 to 5 Poloxamer 407  6 to 20  6 to 20  6 to 20 Methocel E 4M 1 to 2 1 to 2 1 to 2 Purified water qs 100 100 100 

1. A method for treatment of radiomucositis comprising the administration to a mucous membrane of an effective amount of a compound chosen from flavonoids and isoflavonoids in the form of a mixture with a vehicle which is liquid at room temperature and which gels at the temperature of the mucous membrane and which is capable of adhering to the mucous membrane because of its gelled state.
 2. The method of claim 1 wherein administration to the mucous membrane occurs prior to radiotherapy or combined radiochemotherapy.
 3. A pharmaceutical composition for the treatment of radiomucositis comprising an effective quantity of a compound chosen from flavonoids and isoflavonoids in the form of a mixture with a vehicle which is liquid at room temperature and which gels at the temperature of the mucous membrane and which is capable of adhering to the mucous membrane because of its gelled state.
 4. The composition according to claim 3, whose vehicle is an aqueous vehicle and comprises a mixture of 0.05 to 5% by weight of an agent conferring viscosity and of 1 to 20% by weight of an agent modifying the viscosity according to the temperature.
 5. The composition according to claim 4, in which the agent modifying the viscosity according to the temperature is chosen from poloxamers, poloxamines, and divinylbenzenesorbitol compounds.
 6. The composition according to claim 3, whose vehicle is an aqueous vehicle and comprises a mixture of 0.1 to 3% by weight of an agent conferring viscosity and of 5 to 20% by weight of an agent modifying the viscosity according to the temperature.
 7. The composition according to claim 6, in which the agent modifying the viscosity according to the temperature is chosen from poloxamers, poloxamines, and divinylbenzenesorbitol compounds.
 8. The composition according to claim 3, in which the flavonoid is chosen from a rutoside, diosmin, quercitin, tangeretin, and hesperidin.
 9. The composition according to claim 3, in which the isoflavonoid is genistein, daidzin, or glycitin.
 10. The composition according to claim 8, in which the rutoside is rutin.
 11. The composition according to claim 3, wherein the vehicle is water.
 12. The composition according to claim 3 having a viscosity less than 200×10⁻³ Pa·s at 35–37° C.
 13. A pharmaceutical composition for the treatment of radiomucositis comprising from 0.5 to 10% of a rutoside in the form of mixture with a vehicle which is liquid at room temperature and which gels at the temperature of the mucous membrane and which is capable of adhering to the mucous membrane because of its gelled state.
 14. The composition according to claim 13 containing from 2 to 10% of the rutoside.
 15. The composition according to claim 13 containing from 1 to 5% of the rutoside.
 16. The composition according to claim 13 whose vehicle is an aqueous vehicle and comprises a mixture of 0.05% to 5% by weight of an agent conferring viscosity and of 1 to 20% by weight of an agent modifying the viscosity according to the temperature.
 17. The composition according to claim 15 in which the agent modifying the viscosity according to the temperature is chosen from poloxamers, poloxamines, and divinylbenzenesorbitol compounds.
 18. The composition according to claim 13 whose vehicle is an aqueous vehicle and comprises a mixture of 0.1 to 3% by weight of an agent conferring viscosity and of 5 to 20% by weight of an agent modifying the viscosity according to the temperature.
 19. The composition according to claim 17 in which the agent modifying the viscosity according to the temperature is chosen from poloxamers, poloxamines, and divinylbenzenesorbitol compounds.
 20. The composition according to claim 13 in which the flavanoid is chosen from a rutoside, diosmin, quercitin, tangeretin, and hesperidin.
 21. The composition according to claim 13, in which the isoflavonoid is genistein, daidzin, or glycitin.
 22. The composition according to claim 13 in which the rutoside is rutin.
 23. The composition according to claim 13 wherein the vehicle is water.
 24. The composition according to claim 13 having a viscosity less than 22×10⁻³ Pa·s at 35–37° C. 